Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

The Almeida lab has been supported by FCTJPCOFUND/0004/2015; Alzheimer’s Association Research Grant (AARG-19-618007); Maratona da Saúde; H2020 Spreading Excellence and Widening Participation, H2020-WIDESPREAD01-2016-2017-TeamingPhase2-GA739572; iNOVA4Health (UID/Multi/04462/2019), a program financially supported by Fundação para a Ciencia e Tecnologia (FCT)/Ministério da Educação e Ciencia, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. CG’s salary is supported by FCT-CEECIND/00410/2017. FM has been the recipient of an FCT doctoral fellowship (PD/BD/128344/2017). CP has been the recipient of an FCT doctoral fellowship (SFRH/BD/128374/2017).Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by β-amyloid (Aβ) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aβ-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aβ oligomers, highlighting the dysfunction of endocytic trafficking as an Aβ-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo- and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aβ, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aβ and by LOAD genes to disrupt synapses.publishersversionpublishe

How can CEOs influence HRM implementation? Unfolding top management’s role in HRM

This paper investigates how CEOs can influence the implementation of HRM policies in their organizations. It does so by comparing the HRM implementation roles of the same CEO in two different companies as well as those of different CEOs in the same firm. Based on the findings, the study inductively develops a model that describes different types of CEO direct and indirect influence, unfolding the generic label of CEO “support” into a wide catalogue of actions, and identifying further behaviours other than support. The results also challenge some established ideas, such as the view of CEOs’ HRM role solely as strategic decision makers, or that CEO influence necessarily involves overt action. Finally, our findings open several avenues for future research on a relevant and, so far, underdeveloped topic.info:eu-repo/semantics/acceptedVersio

What’s the narrative for practice? A review of recommendations on feedback and a guide to writing impactful practical implications

Research on supervisory feedback has burgeoned over the past twenty years. We ask, what does it have to offer to management practitioners, and is this knowledge conveyed in a constructive way? To answer these questions, we conducted a systematic literature review of the practical implicationscontained in feedback studies. Based on our retained articles (N=120) and using the W-H questions as our guiding framework, we critically discuss: Whyrecommendations are offered, Whatrecommendations are endorsed, Whenand Wherethe recommendations are presented as most applicable, to Whomthose are addressed, and Howthey are framed by researchers. In so doing, we summarize the indicationsthat scientific research has offered to practitioners; moreover, following the same framework and the insights collected via a follow-up survey of academics (N=61), we provide recommendations to researchers across the management and psychology disciplineson how to craft their practical implications sections in a way that may help bridge the gap between research and practice. Keywords: Feedback, systematic review, practical implications, evidence-based management

Spacer effect on heparin-triggered release of a thrombolytic drug from a camouflaged construct

Objective: The purpose of this study is to determine the effect of the polyethylene glycol (PEG) spacer between serum albumin (a camouflaging molecule) and protamine (a binding domain), on the amount of heparin required to release tPA from its inactive construct. Background: Human recombinant tissue plasminogen activator (tPA) is a major thrombolytic drug used for various thrombotic conditions, including myocardial infarction and ischemic stroke. Since the drug may lead to fatal hemorrhagic conditions by depleting clotting factors in blood, targeted prodrug constructs have been proposed to prevent excessive nonspecific plasmin generation. In these constructs, a reversible binding between the drug and a carrier molecule is created, which can be undone by an external trigger. The key to success of this type of strategy is to optimize the strength of the reversible binding, so that the construct is sufficient stable during transit to the target while the external trigger can effectively release the agent. Methods: The tPA and low molecular-weight heparin (LMWH) was conjugated via thiolation chemistry, followed by ion-affinity chromatography. Separately, human serum albumin (SA) and salmine protamine conjugate was prepared via site-specific chemistry. The N-terminus of protamine was thiolated using either succinimidyl 3-(2-pyridyldithio) propionate (SPDP) or the same type of heterobifunctional crosslinker with PEG 34kDa spacer. Following the complexation of the two conjugates, amidolytic activities were spectrophotometrically measured at 405 nm via an indirect chromogenic assay using S-2251, a plasmin-specific substrate in the presence of varying amounts of unfractionated heparin. Results: The tPA activity was fully released from the construct using SA-protamine (no spacer) at the heparin concentration of 0.4 U/mL whereas it took 0.6 U/mL to fully release tPA from the construct using SA-PEG-protamine. Conclusions: The presence of the PEG spacer in the construct resulted in the firmer binding between the LMWH and the protamine moieties from each conjugate, requiring higher concentration of heparin for the full release of tPA activity, compared to the construct without the spacer. For each construct, the heparin concentration required to trigger tPA release was still within the therapeutic range of heparin (0.2-0.7 U/mL). Grant: PFRDG (FY22

Lack of association between Single Nucleotide Polymorphism (rs1400986) in Interleukin-20 Gene and Chronic Hepatitis B Virus Infection

BACKGROUND AND OBJECTIVE: Infection with hepatitis B virus is a major cause of chronic liver diseases and variations within cytokine genes may affect the host immune response to hepatitis B infection. This study was designed to investigate whether IL-20 rs1400986 C/T single nucleotide polymorphism is involved in the progression of chronic hepatitis B infection. METHODS: In this case-control study a total of 150 chronic hepatitis B patients (Anti-HBc Ab positive and HBsAg positive for more than 6 months) and 146 healthy subjects (Anti-HBc Ab and HBsAg negative) among people who were referred to Tehran Taleghani hospital during 2003 to 2005, were examined for differences in genotype and allele frequencies in this case-control study. Polymerase Chain Reaction- Restriction Fragment length Polymorphism (PCR-RFLP) method was applied for analyzing the polymorphism site. FINDINGS: Genotypes Frequency in patients group were CC 32.0% and TT 4.0% in comparison to CT 28.1% and TT 2.7% in control group; however no statistically significant difference was observed in the frequency of IL-20 gene polymorphism (rs1400986) between chronically infected patients and healthy controls for neither allele (P=0.549) nor genotype (p=0.599) frequencies. CONCLUSION: No association was detected between rs1400986 single nucleotide polymorphism within IL-20 gene and chronic hepatitis B infection; thus, this polymorphism appears to have no influence on susceptibility to chronic hepatitis B

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer\u27s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases